Positron emission tomographic studies of brain dopamine and serotonin transporters in abstinent (±)3,4-methylenedioxymethamphetamine (“ecstasy”) users: relationship to cognitive performance

BACKGROUND: (+/-)3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a recreational drug and brain serotonin (5-HT) neurotoxin. Under certain conditions, MDMA can also damage brain dopamine (DA) neurons, at least in rodents. Human MDMA users have been found to have reduced brain 5-HT transporter (SERT) density and cognitive deficits, although it is not known whether these are related. This study sought to determine whether MDMA users who take closely spaced sequential doses, which engender high plasma MDMA concentrations, develop DA transporter (DAT) deficits, in addition to SERT deficits, and whether there is a relationship between transporter binding and cognitive performance. MATERIALS AND METHODS: Sixteen abstinent MDMA users with a history of using sequential MDMA doses (two or more doses over a 3- to 12-h period) and 16 age-, gender-, and education-matched controls participated. Subjects underwent positron emission tomography with the DAT and SERT radioligands, [(11)C]WIN 35,428 and [(11)C]DASB, respectively. Subjects also underwent formal neuropsychiatric testing. RESULTS: MDMA users had reductions in SERT binding in multiple brain regions but no reductions in striatal DAT binding. Memory performance in the aggregate subject population was correlated with SERT binding in the dorsolateral prefrontal cortex, orbitofrontal cortex, and parietal cortex, brain regions implicated in memory function. Prior exposure to MDMA significantly diminished the strength of this relationship. CONCLUSIONS: Use of sequential MDMA doses is associated with lasting decreases in brain SERT, but not DAT. Memory performance is associated with SERT binding in brain regions involved in memory function. Prior MDMA exposure appears to disrupt this relationship. These data are the first to directly relate memory performance to brain SERT density.     

The acute and chronic effects of MDMA ("ecstasy") on cortical 5-HT2A receptors in rat and human brain.

While the pre-synaptic effects of 3,4-methylenedioxymethamphetamine (MDMA) on serotonin (5-HT) neurons have been studied extensively, little is known about its effects on post-synaptic 5-HT(2) receptors. Therefore, cortical 5-HT(2A) receptor densities and 5-HT concentration were studied in MDMA treated rats (10 mg/kg s.c.). Furthermore, 5-HT(2A) post-synaptic receptor densities in the cerebral cortex of recent as well as ex-MDMA users were studied using [123I]R91150 SPECT. In rats we observed a decrease followed by a time-dependent recovery of cortical 5-HT(2A) receptor densities, which was strongly and positively associated with the degree of 5-HT depletion. In recent MDMA users, post-synaptic 5-HT(2A) receptor densities were significantly lower in all cortical areas studied, while 5-HT(2A) receptor densities were significantly higher in the occipital cortex of ex-MDMA users. The combined results of this study suggest a compensatory upregulation of post-synaptic 5-HT(2A) receptors in the occipital cortex of ex-MDMA users due to low synaptic 5-HT levels.     

Radioligands for the study of the 5-HT transporter in vivo

Loss of 5-HT transporter (SERT) sites has been implicated in various neurodegenerative diseases and users of some amphetamine derivatives such as MDMA. Therefore, the development of suitable radioligands for neuroimaging of the SERT in the human brain is important. A large number of drugs have been labeled with 11C, 18F or (123)I over the last ten years in order to achieve such radioligands. Despite these attempts most of the compounds were found unsuitable because of low target-to-nontarget ratios. Some cocaine-derived radioligands allow SERT imaging of the human brain using positron emission tomography (PET) although they have a limited selectivity. Among the various specific 5-HT uptake inhibitors only [(123)I]iodo-nitroquipazine for single photon emission computed tomography (SPECT) and [11C](+)McN5652 for PET appear to meet the criteria of a useful radioligand. There is still a need for the development of new radioligands for SERT imaging. Advances in tracer synthetic methodologies may bring further progress in this field.     

Memory disturbances in ”Ecstasy” users are correlated with an altered brain serotonin neurotransmission

Rationale: Methylenedioxymethamphetamine (MDMA) is known to damage brain pre-synaptic serotonin (5-HT) neurons. Since loss of 5-HT neurons has been implicated in memory loss, it is important to establish whether MDMA use may produce changes in postsynaptic 5-HT receptors and memory function in humans. Objectives: To investigate whether MDMA use leads to compensative alterations in post-synaptic 5-HT_2A receptors and whether there is a relation with memory disturbances. Methods: Brain cortical 5-HT_2A receptor densities were studied with [¹²³I]-5-I-R91150 SPECT in five abstinent MDMA users and nine healthy controls. Memory performance was assessed using RAVLT. Results: [¹²³I]-5-I-R91150 binding ratios were significantly higher in the occipital cortex of MDMA users than in controls, indicating up-regulation. Mean cortical 5-HT_2A receptor binding correlated positively with RAVLT-recall in MDMA users. Conclusion: Our preliminary results may indicate altered 5-HT neuronal function with correlated memory impairment in abstinent MDMA users. Received: 20 August 1999 / Final version: 25 November 1999     

Sustained Recreational Use of Ecstasy Is Associated with Altered Pre and Postsynaptic Markers of Serotonin Transmission in Neocortical Areas: A PET Study with [11C]DASB and [11C]MDL 100907

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT_2A receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT_2A receptors. Positron emission tomography studies using the SERT ligand [¹¹C]DASB and the 5-HT_2A receptor ligand [¹¹C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT_2A receptor availability (binding potential, BP_ND) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP_ND and higher 5-HT_2A receptor BP_ND in cortical, but not subcortical regions. Decreased SERT BP_ND was regionally associated with upregulated 5-HT_2A receptor BP_ND. In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.     

MDMA induces EPSP-Spike potentiation in rat ventral hippocampus in vitro via serotonin and noradrenaline release and coactivation of 5-HT4 and beta1 receptors.

It is well documented that N-methyl-3,4-methylenedioxyamphetamine (MDMA, ecstasy) releases brain serotonin (5-HT; 5-hydroxytryptamine), noradrenaline (NE; norepinephrine), and dopamine, but the consequent effect on brain functioning remains elusive. In this study, we characterized the effects of MDMA on electrically evoked responses in the ventral CA1 region of a rat hippocampal slice preparation. Superfusion with MDMA (10 microM, 30 min) increased the population spike amplitude (PSA) by 48.9+/-31.2% and decreased population spike latency (PSL) by 103+/-139 mus (both: mean+/-SD, n=123; p<0.0001, Wilcoxon test), without affecting field excitatory postsynaptic potential (fEPSP). This effect persisted for at least 1 h after MDMA washout; we have called this EPSP-spike potentiation (ESP) by MDMA, ESP MDMA. Antagonism of GABAergic transmission did not prevent ESP MDMA, suggesting that an increase in excitability of pyramidal cells underlies this MDMA action. Block of serotonin transporter (SERT) with citalopram or 5-HT depletion with (+/-)-p-chlorophenylalanine pretreatment partially inhibited the ESP MDMA. Block of both SERT and NE transporter prevented ESP MDMA, indicating its dependence on release of both 5-HT and NE. ESP MDMA is produced by simultaneous activation of 5-HT4 and beta1 receptors, with a predominant role of 5-HT4 receptors. Block of both 5-HT4 and beta1 receptors revealed an inhibitory component of the MDMA action mediated by 5-HT1A receptor. The concentration range of MDMA which produced ESP MDMA (1-30 microM) corresponds to that commonly reached in human plasma following the ingestion of psychoactive MDMA doses, suggesting that release of both 5-HT and NE, and consequent ESP MDMA may underlie some of the psychoactive effects of MDMA in humans.     

Monoaminergic dysfunction in recreational users of dexamphetamine

Preclinical studies suggest that dexamphetamine (dAMPH) can lead to monoaminergic neurotoxicity. This exploratory study aimed to investigate effects of recreational dAMPH use on the dopamine (DA) and noradrenaline (NA) systems in humans. To that purpose, eight male abstinent dAMPH (26.0±4.0 years) users and 10 age- and IQ-matched male healthy control subjects (23.0±3.8) underwent neuropsychological testing sensitive to DAergic function and single photon emission computed tomography (SPECT) scanning with [¹²³I]FP-CIT to determine striatal DA transporter (DAT) binding. In addition, changes in cerebral blood flow (CBF) induced by the DA/NA reuptake inhibitor methylphenidate (MPH) were measured using pharmacological magnetic resonance imaging (phMRI). Performance of dAMPH users was significantly worse on executive function and verbal memory tasks. Striatal DAT binding ratios were on average lower in dAMPH users (near-significant, p=0.05). In addition, CBF in control subjects decreased significantly in response to MPH in gray matter and basal ganglia, among which the striatum, thalamus and hippocampus by 10% to 29%. However, in dAMPH users the CBF response was blunted in most brain areas studied, only decreasing in the hippocampus and orbitofrontal cortex. When comparing groups, CBF response was found to be significantly different in the thalamus with a decrease for healthy controls and a blunted response in dAMPH users. Collectively, our findings of a blunted hemodynamic response in monoaminergic regions, in combination with indications for lower striatal DAT binding and poorer behavioral measures are likely to represent DAergic dysfunction in dAMPH users, although NAergic dysfunction may also play a role.     

Effects of MDMA and related analogs on plasma 5-HT: relevance to 5-HT transporters in blood and brain

(±)-3,4-Methylenedioxymethamphetamine (MDMA) is an illicit drug that evokes transporter-mediated release of serotonin (5-HT) in the brain. 5-HT transporter (SERT) proteins are also expressed in non-neural tissues (e.g., blood), and evidence suggests that MDMA targets platelet SERT to increase plasma 5-HT. Here we tested two hypotheses related to the effects of MDMA on circulating 5-HT. First, to determine if MDMA metabolites might contribute to actions of the drug in vivo, we used in vitro microdialysis in rat blood specimens to examine the effects of MDMA and its metabolites on plasma 5-HT. Second, to determine whether effects of MDMA on plasma 5-HT might be used as an index of central SERT activity, we carried out in vivo microdialysis in blood and brain after intravenous MDMA administration. The in vitro results show that test drugs evoke dose-related increases in plasma 5-HT ranging from two- to sevenfold above baseline, with MDMA and its metabolite, (±)-3,4-methylenedioxyamphetamine (MDA), producing the largest effects. The ability of MDMA and related analogs to elevate plasma 5-HT is correlated with their potency as SERT substrates in rat brain synaptosomes. The in vivo results reveal that MDMA causes concurrent increases in extracellular 5-HT in blood and brain, but there are substantial individual differences in responsiveness to the drug. Collectively, our findings indicate that MDMA and its metabolites increase plasma 5-HT by a SERT-dependent mechanism, and suggest the possibility that measures of evoked 5-HT release in blood may reflect central SERT activity.     

MDMA and 5-HT neurotoxicity: the empirical evidence for its adverse effects in humans - no need for translation

In this issue of the BJP, Green et al. suggest that animal data could not be used to predict the adverse effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans and that MDMA did not produce 5-HT neurotoxicity in the human brain. This proposal was, however, not accompanied by a review of the empirical evidence in humans. The neuroimaging data on 5-HT markers in abstinent recreational ecstasy/MDMA users are extensive and broadly consistent. Reduced levels of the 5-HT transporter (SERT) have been found by research groups worldwide using a variety of assessment measures. These SERT reductions occur across the higher brain regions and remain after controlling for potential confounds. There are also extensive empirical data for impairments in memory and higher cognition, with the neurocognitive deficits correlating with the extent of SERT loss. Hence, MDMA is clearly damaging to humans, with extensive empirical data for both structural and functional deficits.     

Low striatal serotonin transporter protein in a human polydrug MDMA (ecstasy) user: a case study

Evidence that the widely used methamphetamine analog MDMA (3,4-methylenedioxymethamphetamine, ecstasy) might damage brain serotonin neurones in humans is derived from imaging investigations showing variably decreased binding of radioligands to the serotonin transporter (SERT), a marker of serotonin neurones. However, in humans, it is not known whether low SERT binding reflects actual loss of SERT protein itself. As this question can only be answered in post-mortem brain, we measured protein levels of SERT and that of the rate-limiting serotonin-synthesizing enzyme tryptophan hydroxylase (TPH) in autopsied brain of a high-dose MDMA user. As compared with control values, SERT protein levels were markedly (-48% to -58%) reduced in striatum (caudate, putamen) and occipital cortex and less affected (-25%) in frontal and temporal cortices, whereas TPH protein was severely decreased in caudate and putamen (-68% and -95%, respectively). The magnitude of the striatal SERT protein reduction was greater than the SERT binding decrease typically reported in imaging studies. Although acknowledging limitations of a case study, these findings extend imaging data based on SERT binding and suggest that high-dose MDMA exposure could cause loss of two key protein markers of brain serotonin neurones, a finding compatible with either physical damage to serotonin neurones or downregulation of components therein.     

Validation of [(123)I]beta-CIT SPECT to assess serotonin transporters in vivo in humans: a double-blind, placebo-controlled, crossover study with the selective serotonin reuptake inhibitor citalopram.

Disturbances in the serotonin (5-HT) system are associated with various neuropsychiatric disorders. The 5-HT system can be studied in vivo by measuring 5-HT transporter (SERT) densities using (123)iodine-labeled 2beta-carbomethoxy-3beta(4-iodophenyl)tropane ([(123)I]beta-CIT) and single photon emission computed tomography (SPECT). Validation of this technique is important because [(123)I]beta-CIT does not bind selectively to SERTs. Some studies have validated this technique in vivo in the human brain in SERT-rich areas, but the technique has not been validated yet in SERT-low cortical areas. The aim of this study was to further validate [(123)I]beta-CIT SPECT in assessing SERTs in vivo in humans in both SERT-rich and SERT-low areas. A double-blind, placebo-controlled, crossover design was used with the selective 5-HT reuptake inhibitor (SSRI) citalopram. Six male subjects underwent two [(123)I]beta-CIT SPECT sessions: one after pretreatment with citalopram and one after placebo. Scans were acquired 4 h and 22-27 h p.i., and both region-of-interest and voxel-by-voxel analyses were performed. Citalopram reduced [(123)I]beta-CIT binding ratios in SERT-rich midbrain and (hypo)thalamus. Binding ratios were also lower after citalopram in SERT-low cortical areas, but statistical significance was only reached in several cortical areas using voxel-by-voxel analysis. In addition, citalopram increased binding ratios in the DAT-rich striatum and increased absolute uptake in the cerebellum. The results show that [(123)I]beta-CIT SPECT is a valid technique to study SERT binding in vivo in human brain in SERT-rich areas. Although we provide some evidence that [(123)I]beta-CIT SPECT may be used to measure SERTs in SERT-low cortical areas, these measurements must be interpreted with caution.     

MDMA的神经毒性及SERT mRNA的表达

目的 :探讨MDMA的神经毒性及SERTmRNA的表达。方法 :设立对照组和实验组 ,实验组给予MDMA(2 0mg·kg- 1 ,每日 2次 ,ip ,连续 4d) ,对照组给予等体积生理盐水。采用高效液相色谱法测定不同脑区的DA和 5 -HT含量 ,原位杂交方法检测SERTmRNA的表达。结果 :给予MDMA后 ,大鼠额叶皮层、海马和纹状体的 5 -HT下降 (P <0 0 0 1) ,SERTmRNA的表达明显减少 (P <0 0 0 1)。结论 :MDMA对中枢 5 -HT系统有明显的神经毒性 ,导致SERTmRNA表达下调。     

Effects of cocaine and MDMA self-administration on serotonin transporter availability in monkeys.

Although serotonin (5-HT) can interact with dopamine (DA) systems to modulate the subjective and reinforcing effects of psychostimulants such as cocaine and 3,4-methyldioxymethamphetamine (MDMA, ecstasy), the long-term effects of exposure to psychostimulants on brain 5-HT systems are not well characterized. The present study assessed 5-HT transporter (SERT) availability using positron emission tomography (PET) in rhesus monkeys with the SERT-specific radioligand [(11)C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB). SERT availability was assessed in regions of interest including the caudate nucleus, putamen, anterior cingulate cortex, and cerebellum. [(11)C]DASB distribution volume ratios (DVRs) were calculated using the cerebellum as the reference region. DVRs were calculated in control monkeys and in cocaine or MDMA self-administering monkeys approximately 24 h after the last self-administration (SA) session. SERT availability did not differ between monkeys with a history of MDMA SA and control monkeys in any region examined. In contrast, monkeys with a history of cocaine SA showed significantly higher levels of SERT availability in the caudate nucleus and putamen compared to control subjects. These results suggest that chronic SA of cocaine, but not MDMA, leads to alterations in serotonergic function in brain areas relevant to drug abuse. The higher level of SERT availability in cocaine-experienced monkeys may lead to a reduced inhibitory tone of 5-HT on the DA system, which may explain, in part, differences in the abuse liability between cocaine and MDMA.     

Neuroimaging findings with MDMA/ecstasy: technical aspects, conceptual issues and future prospects

Users of ecstasy (3,4-methylenedioxymethamphetamine; MDMA) may be at risk of developing MDMA-induced injury to the serotonin (5-HT) system. Previously, there were no methods available for directly evaluating the neurotoxic effects of MDMA in the living human brain. However, development of in vivoneuroimaging tools have begun to provide insights into the effects of ecstasy on the human brain. Single photon emission computed tomography (SPECT), positron emission computed tomography (PET) and proton magnetic resonance spectroscopy (1H-MRS) studies which have evaluated ecstasy's neurotoxic potential will be reviewed and discussed in terms of technical aspects, conceptual issues and future prospects. Although PET and SPECT may be limited by several factors such as the low cortical uptake and the use of a non-optimal reference region (cerebellum) the few studies conducted so far provide suggestive evidence that people who heavily use ecstasy are at risk of developing subcortical, and probably also cortical reductions in serotonin transporter (SERT) densities, a marker of 5-HT neurotoxicity. There seem to be dose-dependent and transient reductions in SERT for which females may be more vulnerable than males. 1H-MRS appears to be a less sensitive technique for studying ecstasy's neurotoxic potential. Whether individuals with a relatively low ecstasy exposure also demonstrate loss of SERT needs to be determined. Because most studies have had a retrospective design, in which evidence is indirect and differs in the degree to which any causal links can be implied, longitudinal studies in human ecstasy users are needed to draw definite conclusions.     

Investigating the potential neurotoxicity of Ecstasy (MDMA): an imaging approach

Human users of 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') users may be at risk of developing MDMA-induced neuronal injury. Previously, no methods were available for directly evaluating the neurotoxic effects of MDMA in the living human brain. However, development of in vivo neuroimaging tools has begun to provide insights into the effects of MDMA in the human brain. In this review, contributions of brain imaging studies on the potential neurotoxic effects of MDMA and functional consequences are highlighted. An overview is given of PET, SPECT and MR spectroscopy studies, most of which show evidence of neuronal injury in MDMA users. Different neuroimaging tools are discussed that have investigated potential functional consequences of MDMA-induced 5-HT neurotoxic lesions. Finally, the contribution of brain imaging in future studies is discussed, emphasising the crucial role it will play in our understanding of MDMA's short- and long-term effects in the human brain. Copyright 2001 John Wiley & Sons, Ltd.     

Effects of MDMA on Extracellular Dopamine and Serotonin Levels in Mice Lacking Dopamine and/or Serotonin Transporters

3,4-Methylendioxymethamphetamine (MDMA) has both stimulatory and hallucinogenic properties which make its psychoactive effects unique and different from those of typical psychostimulant and hallucinogenic agents. The present study investigated the effects of MDMA on extracellular dopamine (DA(ex)) and serotonin (5-HT(ex)) levels in the striatum and prefrontal cortex (PFC) using in vivo microdialysis techniques in mice lacking DA transporters (DAT) and/or 5-HT transporters (SERT). subcutaneous injection of MDMA (3, 10 mg/kg) significantly increased striatal DA(ex) in wild-type mice, SERT knockout mice, and DAT knockout mice, but not in DAT/SERT double-knockout mice. The MDMA-induced increase in striatal DA(ex) in SERT knockout mice was significantly less than in wildtype mice. In the PFC, MDMA dose-dependently increased DA(ex) levels in wildtype, DAT knockout, SERT knockout and DAT/SERT double-knockout mice to a similar extent. In contrast, MDMA markedly increased 5-HT(ex) in wildtype and DAT knockout mice and slightly increased 5-HT(ex) in SERT-KO and DAT/SERT double-knockout mice. The results confirm that MDMA acts at both DAT and SERT and increases DA(ex) and 5-HT(ex).     

Altered neuroendocrine and behavioral responses to m-chlorophenylpiperazine in 3,4-methylenedioxymethamphetamine (MDMA) users

Rationale: (±) 3,4-Methylenedioxymethamphetamine (MDMA, ”Ecstasy”) is a popular drug of abuse and a brain serotonin neurotoxin in animals. Growing evidence indicates that humans are also susceptible to MDMA’s neurotoxic effects, although few functional consequences of MDMA-induced 5-HT damage have been identified. Objective: The present study sought to determine whether possible differences between MDMA users and control subjects could be unmasked by utilizing a pharmacological challenge with the mixed 5-HT agonist, meta-chlorophenylpiperazine (m-CPP). It was postulated that 5-HT neurotoxicity in MDMA users would be associated with altered 5-HT responsivity, exemplified by altered physiological and behavioral responses to m-CPP. Methods: Twenty-five MDMA users who had not taken MDMA for at least 3 weeks and 25 controls received intravenous placebo (normal saline) and m-CPP (0.08 mg/kg) in a fixed order, single blind design. Repeated measures of mood, physical symptoms, and blood samples for neuroendocrine analyses were collected during the 90 min after each infusion. Results: MDMA users reported more positive and fewer negative emotions and physical symptoms following m-CPP than controls, and were significantly less likely to report an m-CPP-induced panic attack. Male MDMA users had diminished cortisol and prolactin responses to m-CPP. Conclusions: The present data indicate that MDMA users have alterations in 5-HT neuronal function, possibly as a consequence of MDMA-induced brain serotonin neural injury. Received: 27 January 1999 / Final version: 12 May 1999     

Assessing human 5-HT function in vivo with pharmacoMRI

A number of novel ways of using magnetic resonance imaging (MRI) to visualise the action of drugs on animal and human brain (pharmacoMRI or phMRI) are becoming established tools in translational psychopharmacology. Using drugs with known pharmacology it is possible to investigate how neurotransmitter systems are involved in neural systems engaged by other processes, such as cognitive challenge (modulation phMRI) or to examine the acute effects of the drug itself in the brain (challenge phMRI). In this article we discuss the principles behind phMRI and review studies investigating the effect of serotonin (5-HT) manipulations. 5-HT modulation phMRI studies show the involvement of 5-HT in a broad range of neural processes ranging from motor function through ‘cold’ cognition, such as memory and response inhibition, to emotional processing. We highlight findings in brain areas that show some consistency or complementarity across studies, such as the ventrolateral orbitofrontal cortex where modulation by 5-HT is task-specific, and the amygdala in emotional processing where 5-HT is predominantly inhibitory. 5-HT challenge phMRI is promising but as yet few studies have been carried out. New ways of analysing phMRI data include connectivity analysis which holds the promise of going beyond identifying isolated areas of activation/modulation to understanding functional circuits and their neurochemistry. 5-HT phMRI now needs to be taken into patient populations and methods of investigating treatment effects need to be developed. If this is successful then phMRI will provide a genuinely exciting opportunity for the rapid development of better treatments for psychiatric conditions.     

Memory deficits in abstinent MDMA (ecstasy) users: neuropsychological evidence of frontal dysfunction

Chronic administration of the common club drug 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is associated with long-term depletion of serotonin (5-HT) and loss of 5-HT axons in the brains of rodents and non-human primates, and evidence suggests that recreational MDMA consumption may also affect the human serotonergic system. Moreover, it was consistently shown that abstinent MDMA users have memory deficits. Recently, it was supposed that these deficits are an expression of a temporal or rather hippocampal dysfunction caused by the serotonergic neurotoxicity of MDMA. The aim of this study is to examine the memory deficits of MDMA users neuropsychologically in order to evaluate the role of different brain regions. Nineteen male abstinent MDMA users, 19 male abstinent cannabis users and 19 male drug-naive control subjects were examined with a German version of the Rey Auditory Verbal Learning Test (RAVLT). MDMA users showed widespread and marked verbal memory deficits, compared to drug-naive controls as well as compared to cannabis users, whereas cannabis users did not differ from control subjects in their memory performance. MDMA users revealed impairments in learning, consolidation, recall and recognition. In addition, they also showed a worse recall consistency and strong retroactive interference whereby both measures were previously associated with frontal lobe function. There was a significant correlation between memory performance and the amount of MDMA taken. These results suggest that the memory deficits of MDMA users are not only the result of a temporal or hippocampal dysfunction, but also of a dysfunction of regions within the frontal cortex.     

Chronic administration of THC prevents the behavioral effects of intermittent adolescent MDMA administration and attenuates MDMA-induced hyperthermia and neurotoxicity in rats

Most recreational users of 3, 4-methylenedioxymethamphetamine (MDMA or “ecstasy”) also take cannabis, in part because cannabis can reduce the dysphoric symptoms of the ecstasy come-down such as agitation and insomnia. Although previous animal studies have examined the acute effects of co-administering MDMA and Δ⁹-tetrahydrocannabinol (THC), which is the major psychoactive ingredient in cannabis, research on chronic exposure to this drug combination is lacking. Therefore, the present study was conducted to investigate the effects of chronic adolescent administration of both THC and MDMA on behavior and on regional serotonin transporter (SERT) binding and serotonin (5-HT) concentrations as indices of serotonergic system integrity. Male Sprague-Dawley rats were divided into four drug administration groups: (1) MDMA alone, (2) THC alone, (3) MDMA plus THC, and (4) vehicle controls. MDMA (2 × 10 mg/kg × 4 h) was administered every fifth day from postnatal day (PD) 35 to 60 to simulate intermittent recreational ecstasy use, whereas THC (5 mg/kg) was given once daily over the same time period to simulate heavy cannabis use. THC unexpectedly produced a modest hyperthermic effect when administered alone, but in animals co-treated with both THC and MDMA, there was an attenuation of MDMA-induced hyperthermia on dosing days. Subsequent testing conducted after a drug washout period revealed that THC reduced MDMA-related behavioral changes in the emergence and social interaction tests of anxiety-like behavior and also blunted the MDMA-induced decrease in exploratory behavior in the hole-board test. THC additionally attenuated MDMA -induced decreases in 5-HT levels and in SERT binding in the frontal cortex, parietal cortex, and striatum, but not in the hippocampus. These results suggest that chronic co-administration of THC during adolescence can provide some protection against various adverse physiological, behavioral, and neurochemical effects produced by MDMA.